Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study.

OBJECTIVES: To estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with RA starting MTX. METHODS: Data came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥18 years with physician diagnosed RA and symptom duration ≤2 years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at 6- and 12-month follow-up visits. The period prevalence rates of AEs are reported for 0-6 months, 6-12 months and 0-12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression. RESULTS: A total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematological AEs (5.6%). Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological) and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated glomerular filtration rate and alcohol consumption were associated with less reporting of haematological AEs. CONCLUSIONS: AEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AE occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.

Prevalence and predictors of adverse events with methotrexate mono- and combination-therapy for rheumatoid arthritis: a systematic review.

OBJECTIVES: This systematic review aims to summarize rates of adverse events (AEs) in patients with RA or inflammatory arthritis starting MTX as monotherapy or in combination with other csDMARDs, and to identify reported predictors of AEs. METHODS: Three databases were searched for studies reporting AEs in MTX-naïve patients with RA. Randomized controlled trials (RCTs) and observational cohort studies were included. Prevalence rates of AEs were pooled using random effects meta-analysis, stratified by study design. RESULTS: Forty-six articles (34 RCTs and 12 observational studies) were identified. The pooled prevalence of total AEs was 80.1% in RCTs (95% CI: 73.5, 85.9), compared with 23.1% in observational studies (95% CI: 12.3, 36.0). The pooled prevalence of serious AEs was 9.5% in RCTs (95% CI: 7.4, 11.7), and 2.1% in observational studies (95% CI: 1.0, 3.4). MTX discontinuation due to AEs was higher in observational studies (15.5%, 95% CI: 9.6, 22.3) compared with RCTs (6.7%, 95% CI: 4.7, 8.9). Gastrointestinal events were the most commonly reported AEs (pooled prevalence: 32.7%, 95% CI: 18.5, 48.7). Five studies examined predictors of AEs. RF status, BMI and HAQ score were associated with MTX discontinuation due to AEs; ACPA negativity, smoking and elevated creatinine were associated with increased risk of elevated liver enzymes. CONCLUSION: The review provides an up-to-date overview of the prevalence of AEs associated with MTX in patients with RA. The findings should be communicated to patients to help them make informed choices prior to commencing MTX.

Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid.

OBJECTIVES: Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. METHODS: Biotransformation of resveratrol to its 3-O-glucuronide and 4'-O-glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive-noncompetitive inhibition model. KEY FINDINGS: Probenecid inhibition of resveratrol 3-O-glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki ) averaging 3.1 mm. CONCLUSIONS: The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki ) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans.